Salts of tiotropium with 10-camphorsulfonic acid

Abstract

The present invention relates to novel tiotropium salts with 10-camphorsulphonic acid of formula (I), its optical isomers or their mixtures, their monohydrates, their anhydrous crystalline forms and processes for the preparation thereof, as well as to pharmaceutical compositions containing the same and to the use of novel salts for the treatment of respiratory tract diseases.

1 . Salts of tiotropium with 10-camphorsulphonic acid, its single optical isomers or mixtures thereof 
     
     
         2 . The salt according to  claim 1  with 1S-(+)-10-camphorsulphonic acid. 
     
     
         3 . The salt according to  claim 1  with 1R-(−)-10-camphorsulphonic acid. 
     
     
         4 . The salt according to  claim 1  in a crystalline form. 
     
     
         5 . The salt according to  claim 2  in a crystalline anhydrous form having X-ray powder diffraction pattern (XRPD) with characteristic peaks at 2θ degrees 5.6, 16.4, 17.0, 17.2, 17.3, 18.9, 21.3, and 22.5 (±0.2° θ). 
     
     
         6 . The salt according to  claim 3  in a crystalline anhydrous form having X-ray powder diffraction pattern (XRPD) with characteristic peaks at 20 degrees 5.4, 16.3, 16.9, 17.1, 17.2, 18.7, 21.2, and 22.4 (±0.2° θ). 
     
     
         7 . The salt according to  claim 2  in a monohydrate form. 
     
     
         8 . The salt according to  claim 2  in a crystalline monohydrate form. 
     
     
         9 . The salt according to  claim 3  in a crystalline monohydrate form. 
     
     
         10 . The salt according to  claim 8  having an X-ray powder diffraction pattern (XRPD) with characteristic peaks at 2θ degrees 9.0, 15.6, 17.0, 17.7, 22.0, 25.6, and 27.8 (±0.2° θ). 
     
     
         11 . The salt according to  claim 9  having an X-ray powder diffraction pattern (XRPD) with characteristic peaks at 20 degrees 8.8, 15.4, 16.8, 17.5, 21.8, 25.4, and 27.6 (±0.2° θ). 
     
     
         12 . A process for the preparation of a tiotropium salt with 10-camphorsulphonic acid or a single optical isomer thereof, which comprises quaternization of 9-methyl-3-oxa-9-azatricyclo[3.3.1.0 2,4 ]non-7-yl hydroxy(di-2-thienyl) acetate in an organic solvent selected from a group consisting of nitriles, alcohols, halogenated hydrocarbons, hydrocarbons, esters, ketones, ethers and mixtures thereof, with methyl 10-camphorsulphonate or a single optical isomer thereof, and then isolation of the tiotropium salt. 
     
     
         13 . The process according to  claim 12  wherein the tiotropium salt is isolated in a crystalline anhydrous form. 
     
     
         14 . The process according to claim that wherein the quaternization is carried out in an acetonitrile/methylene chloride mixture. 
     
     
         15 . The process according to  claim 13  wherein the tiotropium salt is isolated by concentration of a reaction mixture to obtain a crystalline residue, followed by addition of an organic solvent to the crystalline residue, trituration, and finally filtration of the crystalline anhydrous tiotropium salt. 
     
     
         16 . The process according to  claim 15  wherein trituration is carried out in methylene chloride or acetone. 
     
     
         17 . A process for the preparation of a crystalline monohydrate of tiotropium salt with 10-camphorsulphonic acid or a single optical isomer thereof characterized in that the salt prepared by the process as claimed in  claim 12  is dissolved in water, preferably at elevated temperature, then the solution is cooled until a crystalline product precipitates and the crystalline product is isolated. 
     
     
         18 . The process according to  claim 17  wherein the salt is dissolved in water at a temperature in the range of 40-90° C., preferably at 70-80° C. 
     
     
         19 . A pharmaceutical composition containing tiotropium salt with 10-camphorsulphonic acid as defined in  claim 1 , and at least one pharmaceutically acceptable carrier(s) and/or pharmaceutical excipient(s). 
     
     
         20 . The method of treating respiratory diseases with tiotropium salts with 10-camphorsulphonic acid, which comprises administration to a patient in need of such treatment of a compound selected from  claim 1  for the treatment of respiratory tract diseases.